Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy

Renato D. Lopes, Patricia O. Guimarães, Bradley J. Kolls, Daniel M. Wojdyla, Cheryl D. Bushnell, Michael Hanna, J. Donald Easton, Laine Thomas, Lars Wallentin, Sana M. Al-Khatib, Claes Held, Pedro Gabriel Melo de Barros e Silva, John H. Alexander, Christopher B. Granger and Hans-Christoph Diener

Key points

  • ICH is a devastating complication of patients with AF receiving oral anticoagulation therapy & is associated with high morbidity & mortality.

  • Nearly 80% of the warfarin-treated patients with ICH had an INR within or below therapeutic range around 2 weeks before the event.


We investigated the frequency and characteristics of intracranial hemorrhage (ICH), factors associated with risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients in ARISTOTLE with ICH who received ≥1 dose of study drug (n=18,140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.2%) versus traumatic (28.8%). Apixaban resulted in significantly less ICH (0.33%/year), regardless of type and location, than warfarin (0.80%/year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th) time from most recent international normalized ratio (INR) to ICH was 13 (6, 21) days. Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale at discharge was ≥4 in 55.7%, and mortality at 30 days was 43.3%. No difference was observed in the rates of all-cause death post-ICH, regardless of treatment. ICH occurred at a rate of 0.80%/year with warfarin regardless of INR control and 0.33%/year with apixaban, and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients with older age.

  • Submitted August 3, 2016.
  • Accepted February 1, 2017.